aa Hoberman 2003a.

Methods	RCT to assess the effectiveness of inactivated influenza vaccine against OM and influenza. 2 groups in 2 following years were randomised before beginning of the respiratory season (1 December to 31 March of each year) to receive 2 doses of vaccine or placebo.
Participants	Children aged 6 to 24 months enrolled at Children Hospital of Pittsburgh. In the first study year, 417 children were enrolled and randomised between 4 October and 30 November 1999 to receive 2 doses of vaccine or placebo. In the second study year, 376 children were randomised between 5 September and 8 December 2000.
Interventions	Children were stratified according to whether they were prone to OM (at least 3 episodes occurred in the last 6 months or 4 in the last year). In the second study year, children were also stratified depending on whether they had received at least 1 dose of pneumococcal conjugate vaccine. Within each stratum, children were randomised in blocks of 9 by means of a computer‐generated list to receive 2 doses of vaccine or placebo in ratio 2:1. The 2 doses were intramuscularly administered approximately 4 weeks apart. First study year: Inactivated trivalent subvirion influenza vaccine (Fluzone, Aventis Pasteur; Swiftwater, PA, USA) containing strains A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), B/Yamanashi/166/98 versus Placebo consisting of a standard diluent and supplied also by Aventis In both years, 2 doses were administered 4 weeks apart. Of the 417 initial participants, 278 were randomised to receive vaccine and 139 to placebo. 5 children in the vaccine group and 1 in the placebo group were discarded because of failure to meet eligibility criteria. The first dose was administered to 273 (vaccine) and 138 (placebo) children. The second dose was administered to 267 and 134 participants, respectively. Second study year: Inactivated trivalent subvirion influenza vaccine (Fluzone, Aventis Pasteur; Swiftwater, PA, USA) containing strains A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Yamanashi/166/98 versus Placebo (standard diluent, Aventis) 1 child from the placebo group was excluded for failure to reach eligibility. 252 children were administered vaccine, 123 placebo. The second dose was administered to 246 and 118 children, respectively.
Outcomes	Serological Seroconversion. 4‐fold increase in antibody titres or postimmunisation titre > 1:40 (before immunisation/4 weeks second dose) Effectiveness First study year: biweekly visit carried out after the second dose of vaccine up to 31 March 2000 (4 months); monthly visits up to 15 November 2000. Second study year: biweekly visits from after second dose was administered (December 2000) up to 31 March 2001 (4 months). Parents were instructed to contact staff for cases of upper respiratory tract infection or otitis. In these cases an interim visit was conducted. Acute care visits: visits resulting from fever (38 °C) within 72 hours or occurrence of otalgia or illness‐related visit to the primary care clinicians. Middle ear effusion: decreased or absent tympanic membrane mobility; yellow or white discolouration of the tympanic membrane; opacification of tympanic membrane not due to scarring; visible bubbles or air‐fluid levels. Outcome is defined as presence of at least 2 symptoms. Acute otitis media: presence of purulent otorrhoea of recent onset not due to otitis externa or middle ear effusion accompanied by 1 or more symptoms: ear pain, marked redness of the tympanic membrane, bulging of the tympanic membrane. Influenza: positive culture obtained from throat swab during visits at which children had upper respiratory tract infection accompanied by fever (38 °C) or acute otitis media or both (during flu seasons: first year 3 January to 15 February 2000; second year 4 January to 30 March 2001). In the first study year, 25 cases occurred during the epidemic and a further 12 in the following 25 weeks of surveillance. In the second study year, the corresponding values were 11 and 2 (16 weeks' surveillance). Safety Minor systemic or local adverse events were not systematically recorded (1 child had 2 brief episodes of unexplained staring on the day of the first vaccination; 1 child had mild intercostals reactions and wheezing 1 day after the second vaccination; 1 child developed acute gastroenteritis 3 days after first vaccination). Other possible adverse were monitored during the care visits.
Funding Source	Industry
Notes	The authors conclude that the vaccine was well tolerated but had no effect on OM, resource consumption, or any of the other indicators.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number, computer‐generated list, block randomisation (block of 9)
Allocation concealment (selection bias)	Low risk	"randomisation lists were kept in locked files not accessible to blinded personnel"
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results.